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2020-03-14
1
Management Algorithms for
Pancreatic Cysts and Intraductal
Papillary mucinous Neoplasms: The Surgeon’s Perspective
PRESENTED BY
JIN-YOUNG JANGDepartment of Surgery, Seoul National University College of Medicine, South Korea
Disclosure of Relevant Financial Relationships
The faculty, committee members, and staff who are in position to control the content of this activity are
required to disclose to USCAP and to learners any relevant financial relationship(s) of the individual or
spouse/partner that have occurred within the last 12 months with any commercial interest(s) whose
products or services are related to the CME content. USCAP has reviewed all disclosures and
resolved or managed all identified conflicts of interest, as applicable.
Professor Jin-Young Jang reported no relevant financial relationships
Content
• Background (Changing concept)
• Comparison of Guidelines
• Consideration Points in Decision of Treatment
• Optimal Indication for Surgery
(Management Algorithm)
Content
• Background (Changing concept)
• Comparison of Guidelines
• Consideration Points in Decision of Treatment
• Optimal Indication for Surgery
(Management Algorithm)
Changes in Epidemiology of Pancreatic Cyst
2.2% of normal population
Chang and Jang, Medicine 2016Klibansky DA, et al.,
Clin Gastroenterol Hepatol 2012
Age & sex-adjusted incidence; 0.31 4.35/100,000 (↑14 fold)
MCNSCN
IndetermiateIPMN
0
25
50
75
100
125
150
20's 30's 40's 50's 60's 70's 80's
Patients Number and Types/Size of IPMN
Gaujoux S et al. J Am Coll Surg 2011;212:590–600
BD, 84
Mixed, 14
MD, 2
SNUH (Unpublished
data)N=2,834
2020-03-14
2
SCN MCN SPN IPMN
Observation
No Yes
Sx/Cx
DDX (?)
Yes No
No Sx/Cx
Branch-type ≤3 cm
Mural nodule(-)
>3 cm Mural nodule(+) Main duct dilatation
↑ Tumor marker
Surgical Indication
Surgery
Malignancy Potential and Survival
Nilsson et al. Pancreas 2016 (Systematic review), Park & Jang. Pancreatology 2014
MCN0~34% of resected MCNs are associated with invasive cancer
Lesions <4cm: malignancy 0.03%Goh et al. World J Surg 2006
5YSR 76%
Clinical Characteristics
Jais et al. Gut 2016
SCN
Tumour size and growth rate Three serous cystadenocarcinomas (0.1%)
N=2,622 from 71 multicenters, 23 nations
Growth rate
<4 cm: 1.25 mm/yr
≥4 cm : 2.7mm/yr
Case
- F/71
- Indigestion
2008.9
2013. 4 SCN
SPN
Kang et al. Ann Surg 2014
N=351, Korean multi-centers study
Malignant features (28%)
- invasion to adjacent tissues, perineural/lymphovascular invasion, -
- metastasis (4%)
Malignancy Potential and Survival SPN
Kang et al. Ann Surg 2014
N=351, Korean multi-centers study
Malignant features (28%)
Tumor size and age
Survival according to malignancy
Malignancy Potential and Survival
2020-03-14
3
Aggressive Conservative
Surgical mortalityMedical mortality(Cancer Conversion)
International Consensus (15 years ago)
• W. Traverso : The survival curves between invasive
IPMN and ductal adenocarcinoma are the same!! We
should resect IPMN before they become invasive.
• M. Buchler: We operate all, branch type IPMN except
malignancy with nonresectable situation or
metastasis....
• C.Yeo : We have been resecting healthy folks with
presumed side branch IPMNs. less than 20% are
observed.
Content
• Background (Changing concept)
• Comparison of Guidelines
• Consideration Points in Decision of Treatment
• Optimal Indication for Surgery
(Management Algorithm)
0
50
100
150
200
250 Description of mucin-producing pancreatic carcinoma:
Ohhashi et al. Prog Dig Endo 1982
1st 2nd
Established disease entity
by WHO
3rd
Consensus IAP guideline
Numbers of Publication on IPMN
Definition of
Main duct type
> 10mm
International Association of
Pancreatology
2020-03-14
4
Surgical Indication of IPMN
-main duct dilatation(+) -cyst >30mm
-mural nodule(+) -cytology (+)Expert opinion
Tanaka et al. Pancreatology 2006
2016
2017
2012
Key Roles in International Consensus
Guidelines on IPMN
2nd
3rd
Treatment Guidelines on IPMN
Authors(Organization)
Year Titles or Subject
Hruban 2004 Pathologic consensus
Tanaka (IAP) 2006 Guideline on Diagnosis & Treatment
SSAT 2007 Guidelines on Cystic neoplasms of the pancreas
Tanaka (IAP) 2012 2nd Guideline
Del Chiaro 2013 European experts consensus
Buscarini 2014 Italian guideline
Vege (AGA) 2015 American Gastroenterological Association
Adsay 2016 Revision on pathologic consensus guideline
Tanaka (IAP) 2017 3rd Guideline
Del Chiaro 2018 2nd European Guideline
Guideline Absolute indication for
Surgery
Relative indication for
Surgery
European 2018 • Jaundice
• Enhancing nodule ≥ 5mm• MPD ≥ 10mm
• Positive Cytology
• pancreatitis
• Cyst size >4cm• 5 ≤ MPD ≤ 9mm
• New DM
• Enhancing mural nodule (<5mm)
• Rapid growing cyst
• Elevated serum CA19-9
IAP 2012/2017 • Jaundice
• Enhancing nodule ≥ 5mm• MPD ≥ 10mm
• Positive Cytology
• Cyst ≥ 3cm
• Thickened/enhancing cyst wall• 5 ≤ MPD ≤ 9mm
• Non-enhancing mural nodule
• Abrupt change in p-duct
• Rapid growing cyst
• Elevated serum CA19-9
AGA 2015 • Symptomatic
• Solid component andMPD >5mm
• Positive Cytology
• Cyst≥ 3cm
• MPD dilatation• Mural nodule
Conservative
Comparison of Guidelines on IPMN
Require 2 features
for EUS
Cystic Fluid Cytology
• Specificity 83%
• Sensitivity 35%
• Accuracy 59%Brugge et al. Gastroenterol 2004
Needs Invasive procedures
• 33% Inadequate or non-diagnostic
Data from Mount Sinai (Scapel et al.)
Guideline Absolute indication for
Surgery
Relative indication for
Surgery
European 2018 • Jaundice
• Enhancing nodule ≥ 5mm• MPD ≥ 10mm
• Positive Cytology
• pancreatitis
• Cyst size >4cm• 5 ≤ MPD ≤ 9mm
• New DM
• Enhancing mural nodule (<5mm)
• Rapid growing cyst
• Elevated serum CA19-9
IAP 2012/2017 • Jaundice
• Enhancing nodule ≥ 5mm• MPD ≥ 10mm
• Positive Cytology
• Cyst ≥ 3cm
• Thickened/enhancing cyst wall• 5 ≤ MPD ≤ 9mm
• Non-enhancing mural nodule
• Abrupt change in p-duct
• Rapid growing cyst
• Elevated serum CA19-9
AGA 2015 • Symptomatic
• Solid component andMPD >5mm
• Positive Cytology
• Cyst≥ 3cm
• MPD dilatation• Mural nodule
Conservative
Comparison of Guidelines on IPMN
Require 2 features
for EUSDiscontinuation of surveillance after 5 year if there is no change
2020-03-14
5
Long-term risk of malignancy in BD-IPMN
Oyama et al. Gastroenterol 2020
• Jan. 1994 ~ Dec. 2017 (20 years)
• Single institution (Univ. of Tokyo)
3.3%
6.6%
Cumulative Malignancy Rate
15%
Annual Malignancy
Rate: 0.7%
Sensitivity and Specificity of Clinical
Guidelines on IPMN
Sensitivity % Specificity %
AGA
with required cytology7.3 88.2
IAP 73.2 45.6
Xu et al. Medicine 2017
Examples
76 year, male
Tumor size (mm) 16 42 42
MPD (mm) 4 2 9
Mural nodule + - -
CA19-9 45 17 12
European Resection Resection Resection
IAP Resection Observation Resection
AGA Observation Observation EUS/Observation
73 year, male
44444307 유병남 51117526 김현주 43523803 최각수
75 year, male Content
• Background (Changing concept)
• Comparison of Guidelines
• Consideration Points in Decision of Treatment
• Optimal Indication for Surgery
(Management Algorithm)
[Disease factors]
Natural history
Malignant potential
Symptom/sign
Extent of the disease
Location
Observation Resection
Interval
Method
How long ?
Extent Limited (organ preserving)
Conventional
Method Open
Laparoscopic
[Host factors]
Age
Co-morbidity
Life expectancy
Op. risk
Pancreas function
Medical accessibility
[ETC]
Efficacy
Mobidity/Mortality
Safety
Longterm effect
Medical cost
Opportunity cost
Considering factors
58%
9%
63%
15%
Longitudinal risk of at least HGD or IC is time-dependent.
Patients with branch duct IPMN present a much lower risk,
justifying a nonoperative surveillance.
Duration since 1st sign (months)
2 years
LEVY et al. Clin Gastroenterol Hepatol. 2006
Malignancy rate
according to the type
Main duct type: 45-92% (60%)
The majority are candidates for
resection
Branch duct type: 5-50% (20%)
Observation vs Surgery
(optimal indication?)
Annual Malignancy Rate: 2~3%
Natural History of IPMN
2020-03-14
6
Annual growth rate
0.6 ± 0.9 mm/yr
FU duration (month)
Patient with suspicion of
IPMN (n=10,083)
Uncertain diagnosis (n=4,566)
Eligible patient (n=1,369)
Main duct type (n=47)
Follow up <3year (n=3630)
Only sono f/u (n=473)
Diagnosed as IPMN
(n=5,519)
• 2001-2016
• Followed up duration over 3 yrs• CT/MRI or EUS
-a pleomorphic cyst
-a clubbed, finger-like cyst
-duct communication (+)
• Supervised by Radiologist
Natural History & Surveillance of IPMN
Median f/u
60m
Han & Jang. Gastroenterol 2019
Size 10Y worrisome
feature (+)
≥3cm 83.1%
2≤ <3 69.6%
Total1≤ <2
23.2%20%
< 1cm 7.3%
Appearance of Worrisome Features
During Surveillance in BD & Mixed IPMN
Han & Jang. Gastroenterol 2018
Size 10Y
MalignancyRate (%)
≥3cm 13.1%
2≤ <3 12.8%
Total1≤ <2
1.8%1%
< 1cm 0%
0.2% annual risk
1~2% annual risk
Malignancy Rate During Surveillance
in BD & Mixed IPMN
Han & Jang. Gastroenterol 2018
Optimal Surveillance Interval Based on Growth Rate & Cyst Size
G1
(0-9.9mm)
G2
(10-19.9mm)
G3
(20-29.9mm)
G4
(over 30mm)
N 667 608 84 10
Cyst size(mm) 7.0 ± 1.9 13.4 ± 2.6 23.3 ± 2.7 34.1 ± 9.4
Growth rate (mm/yr)
Max. growth rate
95% CI
0.6 ± 0.7
6.9
2
0.5 ± 0.9
7.3
2.3
1.0 ± 1.5
9.3
3.9
1.0 ± 1.2
3.3
3.3
Doubling time (yr)
Shortest doubling time
95% CI
11
1
3.6
26
1.8
5.8
23
2.5
5.9
34
11.2
11
50% increasing time (yr)
Shortest 50% inc.
95% CI
5
0.5 (6month)
1.8
13
0.9 (10month)
2.9
11
1.3
3.0
17
5.6
5.5
Time for being 3cm cyst
Shortest time(yr)
95% CI
38
3.3
11.6
33
2.3
7.1
6
0.7
1.7
Recommended follow up
(yr)
6month -> 2yr 6month x2
-> 2yr
6month x 2
-> 1yr
Han & Jang. Gastroenterol 2018
Revised Surveillance Program by IAP 2017
Tanaka et al. Pancreatology 2017
6month
-> 2yr
6month x2
-> 2yr
6month x 2
-> 1yr
6month
Recommended follow up interval
Hu et al. JAMA Surgery 2019
4.25 yr
Early resection
Surveillance
2020-03-14
7
• Surveillance Strategymust spend >$20,000 /patient to improve quality adjusted life
year (QALY)
• Surgery Strategy$132,436/QALY
Least deaths from PDAC
(5.4%),
but 4.7% died due to
the surgery
Budde et al. Visceral Medicine 2015
The Clinical and Socio-Economic Relevance of Increased IPMN Detection Rates and Management Choices
• Surveillance Strategymust spend >$20,000 /patient to improve quality adjusted life
year (QALY)
• Surgery Strategy$132,436/QALY
Least deaths from PDAC
(5.4%),
but 4.7% died due to
the surgery
Budde et al. Visceral Medicine 2015
The Clinical and Socio-Economic Relevance of Increased IPMN Detection Rates and Management Choices
hospital mortality and PD volume
Hyder et al. JAMA Surgery 2013
Meta-analytic estimates of the cumulative incidence of
malignancy during follow-up
Choi et al. Clin Gastroenterol Hepatol. 2017
-AGA systematic review-
5YSR of invasive IPMN: 40%
Vege et al, Gastroenterol 2015
99.8
91.0
81.4
72.6 67.0 66.8
40.0
26.7 26.7
8.0
0
10
20
30
40
50
60
70
80
90
100
5 year survival rate
National Cancer Center, Korea, 2013
Malignancy Potential and Survival
Criteria for Resection in BD-IPMN
1st Consensus
Guideline (2006)
>3cm
Mural nodule (+)
Duct dilatation
Cytology (+)
Symptomatic
2nd Consensus Guideline
(2012)
>3cm
Mural nodule (+)
Duct dilatation > 5 mm
Thickened enhanced cyst walls
Abrupt change in the MPD caliber
with distal pancreatic atrophy
Lymphadenopathy
Cytology (+)
High-risk stigmata MPD >10 mm Enhanced solid component
worrisome feature
Tanaka et al. Pancreatology 2006, 2012
Revised Criteria for Malignancy Predicting Factors
>3cm Mural nodule (+) Duct dilatation > 5 mm Thickened enhanced cyst walls Abrupt change in the MPD caliber with distal pancreatic atrophy Lymphadenopathy
High-risk stigmata Obstructive jaundice
MPD >10 mm
Enhanced mural nodule
Worrisome features
2nd Consensus Guideline (2012)
>3cm Mural nodule (+) Duct dilatation > 5 mm Thickened enhanced cyst walls Abrupt change in the MPD caliber with distal pancreatic atrophy Lymphadenopathy Increased serum CA19-9 Cyst growth rate >5mm/2 yrs
High-risk stigmata Obstructive jaundice
MPD >10 mm
Enhanced mural nodule >5mm
Worrisome feature
Revised Consensus Guideline (2017)
Tanaka et al. Pancreatology 2012, 2017
2020-03-14
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P value Sensitivity(%) Specificity(%) PPV(%) NPV(%) Accuracy(%) HR 95% CI P value
Cyst size (≥3cm) 0.057 56.1 53.7 37.4 71.2 54.5
MPD (>5mm) 0.001 54.7 78.0 55.1 77.7 70.3 5.32 2.67 – 10.60 0.001
Mural nodule 0.001 62.8 87.3 71.0 82.7 79.2 9.12 4.60 – 18.09 0.001
Thickened cystic wall 0.001 38.5 89.7 65.0 74.5 72.7 3.40 1.51 – 7.63 0.003
Abrupt change in
MPD diameter
0.001 19.3 95.9 70.3 70.5 70.4 2.45 0.78 – 7.94 0.124
Lymphadenopathy 0.002 5.2 99.6 87.5 67.8 68.2 3.79 0.31 – 46.74 0.298
CEA (>5ng/mL) 0.046 6.8 97.7 60.0 67.6 67.3 2.90 0.80 – 10.45 0.104
CA 19-9 (>37 U/mL) 0.001 34.9 92.3 69.9 73.5 72.9 5.25 2.05 – 13.42 0.001
Cyst growth rate
(>5mm/2year)†
0.012 60.9 70.3 42.4 83.3 67.8 3.68 0.001
Comparison of diagnostic performance between 2017 and 2012 ICG
AUC LR SVM1 SVM2 SVM3 RF
2012 IAP 0.746 0.650 0.650 0.650 0.758
2017 IAP 0.784 0.680 0.686 0.684 0.787Ricci et al.
Pancreas 2016
Clinical Validation of the 2017 International Consensus
Guidelines on IPMN
Kang & Jang.
Ann Surg Treat & research 2019
Biomarkers Predicting Malignancy
Springer et al. Gastroenterology 2015
Content
• Background (Changing concept)
• Comparison of Guidelines
• Consideration Points in Decision of Treatment
• Optimal Indication for Surgery
(Management Algorithm)
Hazard Ratio ofMalignancy Predicting
Factors
VariablesHazard r
atio95% CI p-value
MPD>5mm 4.5382.449-
8.408<0.001
Mural nodule 6.2673.271-
12.009<0.001
Thickened cyst wall 1.5490.756-
3.1700.231
Lymphadenopathy 4.9660.478-
51.6230.180
CA19-9>37U/mL 4.0321.826-
8.9030.001
Jang et al. Br J Surg 2014
Number
Of
Risk Factors
Benign
(n=253)
Malignant
(n=97)
Accuracy
(%)
0 71 3 (4%)
1 122 29 (19%) 44.4
2 41 22 (35%) 67.9
3 11 22 (67%) 86.9
≥4 8 21 (72%) 89.3
Additive Effect of Malignancy Predicting
Factors
Personalized approach for IPMN
to predict malignancy risk quantitatively in BD-IPMN
considering different statistical value of several variables
Diagnostic tools (Nomogram) is needed
Malignancy Risk Score • Tumor size
• Duct diameter
• Mural nodule
• Tumor marker
• Symptoms, etc
Individual
findings
Korea-Japan
1st International
collaboration study
BD-IPMN (n=2,258)
- Main duct diameter
>10mm (n=225)- Insufficient/incorrect
data (n=5)
Initial enrolled
patients (n=2,488)
Ann Surg 2017;266:1062
2020-03-14
9
Model development – Internal validation
60years: 42
CEA 2: 7
CA19-9 67: 60
MPD 6mm: 48
size 35mm: 20
Mural nodule (+): 52
Total 229= 59%
Indication for resection
Evaluate performance – External validation
20% interval quantile 10% interval quantile
Hosmer-Lemeshow p-value : 1.31e-01 Hosmer-Lemeshow p-value : 2.22e-01
Calibration plot
• 1,000 times boot-strapped Calibration
Jang et al. Ann Surg 2017
http://statgen.snu.ac.kr/software/nomogramIPMN
Jang et al. Ann Surg 2017
Global Validation of Nomogram Predicting Malignancy
Europe - Karolinska U- Academic Medical Center
- Verona U
USA- Johns Hopkins
- Columbia U
China - Peking U- Fudan U
Taiwan- National Taiwan U- Taipei Veterans H
External Validation - Malignancy prediction
All
AUC 0.776
All
Cut-off 0.346
Sensitivity 0.712
Specificity 0.736
Balance 0.724
Cf) AUC : 0.783(Previous validation)
Predictive accuracy for All patients
Jung et al. Br J Surg 2019
Survival according to Pathology and Nomogram
Han and Jang. NEJM (Submitted)
2020-03-14
10
Life Expectancy and Quality Adjusted Life Year according to treatment (Surgery vs Surveillance) Using Nomogram
AgeMalignancy
risk
Life Expectancy QALY
Surveillance
Surgery
(Mortality
1%)
Surgery
(Mortality
3%)
Surgery
(Mortality
5%)
Surveillance
Surgery
(Mortality
1%)
Surgery
(Mortality
3%)
Surgery
(Mortality
5%)
<65
<10% 13.29 12.43 12.06 11.81 13.29 12.08 12.00 11.75
10~35% 10.98 12.13 11.76 11.52 10.98 11.51 11.70 11.46
>35% 5.79 12.61 12.23 11.98 5.31 12.54 12.17 11.91
65≦Age<75
<10% 11.27 12.56 12.18 11.93 11.27 12.44 12.02 11.77
10~35% 8.33 10.46 10.15 9.94 8.33 10.32 10.07 9.86
>35% 6.96 8.65 8.39 8.22 6.38 8.14 8.33 8.16
≧75
<10% 9.25 10.18 9.86 9.72 9.25 10.09 9.77 9.43
10~35% 7.41 8.07 7.83 7.67 7.41 7.95 7.83 7.67
>35% 4.06 5.30 5.14 5.03 3.72 5.00 5.08 4.97
Less than 1 year More than 1 year
Less than 1.5 years More than 1.5 years Han and Jang. NEJM (Gastroenterol)
Examples 76 year, male
Tumor size (mm) 16 40 42
MPD (mm) 4 2 10
Mural nodule + - -
CA19-9 45 17 12
Malignancy risk 47.5% 17.9% 44.4%
Invasive risk 21.6% 6.3% 15.2%
Final pathology T1N0 invasive Low grade dysplasia T2N1 invasive
73 year, male
44444307 유병남 51117526 김현주 43523803 최각수
75 year, male
Treatment Algorithm
No
Yes
Surgery
SurveillanceNomogram
Symptomatic orHigh Risk Stigmata
Worrisome features
No
• Enhancing solid component ≥ 5mm
• MPD ≥ 10mm
• Positive cytology
Yes
Malignancy
Risk
>30~40%
YesNo
<10 mm 10≤ <20 mm 20 ≤ <30 mm ≥ 30 mm
Malignant features (+) or rapid progression
CT/MRI
Initial 6 months
→ 2 years
CT/MRI
Biannual,
6 months interval
for 1 year
→ 1.5- 2 years
MRI/EUS
Biannual,
6 months interval
for 1 year
1 year
Close
surveillance
MRI/EUS
Every 6 months
According to cyst size
Summary & ConclusionDetection of small IPMN has been increasing.
Most of BD-IPMN are dormant. Annual malignancy conversion rate 0.2~0.6%.
But large cyst over 3cm or growing BD-IPMN must be carefully monitored due to the increasing risk of
malignancy.
Three guidelines have controversies on some issues due to lack of evidences.
needs more evidences in a future.
Tailored approach is needed in selection of surgery or surveillance
considering malignancy potential and patient’s factors. Nomogram could be
a valuable tool in selecting treatment methods as customized approach for
IPMN